In contrast to other sensory modalities such as vision and hearing, pain is, by definition, unpleasant at threshold. This unpleasantness is the subjective correlate of a drive to escape and avoid tissue damaging stimuli. Although the clinical importance of the affective-motivational aspect of pain is generally accepted, the lack of a valid animal model has hampered investigation of its neurobiological basis. The research propose din this project is specifically designed to examine the neural mechanisms of aversion produced by noxious stimuli. We will adapt the place preference apparatus to measure the magnitude of aversion to a context associated with a hindpaw formalin injection (conditioned place aversion or CPA). Rats will receive formalin in a compartment with obvious olfactory, visual and tactile cues. On alternative days they will receive saline in a second compartment. After formalin conditioning, the reduction of time spent in the formalin-associated compartment will be taken as a measure of aversiveness. The effects of formalin elicited CPA of inactivating various CNS structures implicated in nociception will be studied. In the first experiments rats will receive a substance P receptor neurotoxin, the Substance P-saporin conjugate, in the lumbar intrathecal space to selective destroy lamina I spinomesencephalic and spinothalamic neurons. If this reduces CPA, rats will be tested for the effects of lesions or transient inactivation of the parabrachial nucleus and of spinothalamic target nuclei and cortical areas activated by noxious stimuli. Thalamic areas to be studied include the Ventrobasal Complex, the posterior thalamic/posterior intralaminar group, and the medial thalamic/intralaminar region The cortical areas to be studied include the somatosensory, anterior cingulate and dysgranular insular corteces. In complementary studies, cortical areas implicated in aversion by inactivation in aversion by inactivation studies will be stimulated using excitatory chemical agents to determine if local neuronal activity can elicit CPA in the absence of a peripheral noxious stimulus. Finally, we will study the effect on formalin behaviors and CPA of reversible inactivation of descending modulatory systems.